Despite an almost 50% decline in the incidence of the sudden infant death syndrome (SIDS) following the 1992 national recommendation for the supine sleep position, SIDS remains the leading cause of postneonatal infant mortality in the United States. Its overall incidence is 0.6/1000 live births. Based upon the program project's first cycle, we hypothesize that a neurological subset of SIDS cases is due to developmental abnormalities in the medullary 5-HT system that interfere with protective homeostatic responses to potentially life-threatening, but often occurring, events during infant sleep, such as hypoxia, hypercarbia, asphyxia, thermal stresses, blood pressure changes, and/or reflex apnea. By "medullary 5-HT system", we mean an inter-related group of 5-HT and non-5-HT neurons in the raphe' and extra-raphe' reticular formation and ventral surface of the medulla that influence homeostatic functions, i.e., respiration, chemosensitivity to carbon dioxide and oxygen, upper airway reflexes, blood pressure control, heart rate, thermoregulation, and sleep. The overall goal of the proposed second cycle is to define in-depth the organization, function, and development of the medullary 5-HT system, the mechanism(s) by which its dysfunction results in sudden death, and potential causes of this dysfunction. In Project 1, we will analyze the neurochemical organization of the medullary 5-HT system in early human life, and we will further characterize its pathology in SIDS cases. In Project 2, we will define the neurochemieal organization of the medullary 5-HT system in the piglet, a model of human infant homeostatic physiology, and we will examine the effects of specific neuronal disruptions within it on central chemosensitivity, respiration, and upper airway control in the piglet. In Project 3, we will examine the effects of disruptions in the medullary 5-HT system upon sleep, thermal stress responses, and cardiorespiratory stability in the piglet. In Project 4, we will study the rote of the medullary 5-HT system in neurogenesis, eupnea, and gasping in the reduced preparation of the rat brainstem. In Project 5, we will study cellular mechanisms underlying Chemosensitivity and their development medullary 5-HT neurons in vitro. In Project 6, we will examine the prenatal development of the medullary 5-HT system with fate mapping tools in genetically engineered mice. In Projects 1, 4, 5, and 6, we will examine aspects of the corollary hypothesis that exposure to nicotine (a major toxic component of cigarette smoke) alters the prenatal development of the medullary 5-HT system, increasing the postnatal risk for SIDS. The six projects will be served by three core units: an Administrative Core (A), an Anatomy Core (B) and a Whole Animal Physiology Core (C). The proposed studies should provide important insights into the role of the medullary 5-HT system in homeostatic control and in sudden infant death that will be critical in the design of specific interventions (e.g., drugs) to prevent or ameliorate medullary 5-HT dysfunction in affected SIDS infants.